Cardiovascular disease (CVD) risk estimation has historically focused on outpatient data from whites according to age, sex, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), diabetes, smoking, and blood pressure (BP) information. Risk factors (RFs) and overall CVD risk are associated with genetic variations in genome-wide association studies (GWAS), and phenotypes have largely been based on single RF measurements using a Framingham approach. Previous research has focused on European Americans (EA), and generally has not included Veterans. Little information on CVD risk factor genes is available for African Americans (AA) or Hispanic Americans (HA), two population groups that are extremely important in the VA. The Million Veteran Program (MVP) cohort provides a unique opportunity to study genes and CVD risk among these subgroups, using MVP questionnaire data, electronic health record (EHR) information, and genetic data. We propose to address scientific gaps by focusing on multiple ethnicities, rare variants, and antecedent RF levels using the MVP cohort. In previous funding we created a virtual baseline exam for all MVP participants and we propose to further curate that information, extend research into new heart disease RFs and conditions, and use a longitudinal prospective study design. In addition to traditional CVD RFs such as lipids, smoking, diabetes, and BP that are already under investigation by our MVP research group, we propose to use GWAS to assess effects of genes on blood cell indices, inflammatory conditions, valvular heart disease, obstructive sleep apnea, and atrial fibrillation. Our research will assess gene-environment (diet quality, pharmacological treatment) effects, and will included assessment of current and antecedent RF levels. Methods will include diet quality adjustments using the Willett Food Frequency Questionnaire performed at the MVP baseline visit. Other methods will include pharmacologic treatment of CVD RFs to derive imputed untreated RF levels, and antecedent quantitative CVD RFs measured at VA outpatient visits up to 14 years before the MVP baseline visit when such data are available. We will perform common variant association studies (CVAS) and rare variant association studies (RVAS), testing for the association of genetic variants to quantitative CVD risk for incidence and period prevalence of a) coronary heart disease (CHD) [myocardial infarction (MI), coronary bypass grafting (CABG), percutaneous coronary intervention (PCI)] and b) atherothrombotic stroke, with comparison of effects by race and ethnicity, and c) recurrent events following an initial MI or stroke. Summary analyses will examine the multigenic association of CHD and stroke using the genetic risk score (GRS) of validated CVD-associated SNPs within and across ethnicity. This project will provide a platform for CVD incidence analyses for MVP participants across the VA in the future. The proposed study findings will allow for the comparison of the impact of genetic variants on heart disease RFs and atherosclerotic disease prevalence across AA, HA, and EA Veterans.